Analysis of non-radial interneuron migration dynamics and its disruption in Lis1+/- mice

Cell migration is an integral process in neural development. Analyses of radial cell migration (RCM) have revealed three modes of migration and specific defects in migration in various mouse mutants. In contrast, the dynamics of non-radial cell migration (NRCM) are incompletely understood. To investigate the dynamics of NRCM, we utilized a slice culture assay coupled with time-lapse videomicroscopy. This analysis revealed that non-radially migrating cells have a complex pattern of extending and retracting one or multiple processes while the nucleus advances concurrently or independently. These data indicate that the process of interneuron migration is unique to that seen for any mode of RCM. Non-radially migrating neurons moved for an average of 0.85 microm/min and paused for approximately 14% of the time observed. Given the novel morphology of NRCM, we hypothesized that specific aspects of migration would be defective with mutations in known cell migration genes, as described for RCM. This was tested by examining the dynamics of migration in the Lis1 mutant mouse; a well-defined cell migration mutant with known defects in NRCM. In contrast to wild-type cells, the rate of nuclear movement was significantly reduced in Lis1+/- interneurons, whereas the rate of active leading edge movement was similar. Morphologically, the leading process was significantly longer and the number of branches reduced in Lis1+/- mice. Together, these data indicate that the NRCM defect in Lis1+/- mice affects specific cellular processes. These data provide insight into NRCM and practical methods for future studies on the role(s) of specific genes in interneuron migration.